Arginase and the Aging Cardiovascular System

描述（由申请人提供）：异常内皮NO血管舒张机制有助于增加老年心血管系统的心血管风险。由于L-精氨酸的细胞内浓度远远超过一氧化氮合酶（NOS）的Kd，因此NO合酶底物L-精氨酸通过未知机制改善内皮依赖性血管舒张。即使在细胞中明显足够的L-精氨酸水平的情况下，L-精氨酸给药增加NO合成并增强内皮功能的观察结果被称为"L-精氨酸悖论"。精氨酸酶，尿素循环的酶，也使用L-精氨酸作为底物，存在于心血管组织中。我们的初步数据表明，L-精氨酸代谢酶，精氨酸酶，调节血管内皮NOS活性，并直接影响血管舒张大鼠。此外，在老龄大鼠血管中，过氧化物酶活性和表达增加，并且过氧化物酶抑制剂减弱了老龄大鼠血管组织中产生的增加的活性氧（ROS）。我们假设：1）内皮细胞脱氨酶通过竞争细胞内L-精氨酸限制内皮细胞NO的产生，从而限制内皮依赖性血管舒张; 2）衰老的血管内皮功能障碍与内皮细胞脱氨酶表达的增加有关，并且脱氨酶的抑制将NO依赖性信号传导和内皮功能恢复到年轻表型的水平; 3）相对底物（L-精氨酸）缺乏增强ROS产生，通过改变NO和O2-之间的平衡进一步损害内皮功能;和4）慢性精氨酸酶抑制将恢复精氨酸反应性，增强NO信号传导，并减少ROS的产生，从而恢复改变的综合心血管参数（增加的血管和心室硬度和改变的心室动脉耦合）的年轻表型。我们将研究的调节作用，在正常的内皮功能和NO信号，以及它的作用，与衰老相关的内皮功能障碍的病理生理。这些实验将提供对NO信号传导途径的调节以及内皮功能中NO和O2-之间的平衡的新见解，对以内皮功能障碍为特征的多种病症具有重要的治疗意义。

DESCRIPTION (provided by applicant): Abnormal endothelial NO vasodilator mechanisms contribute to increased cardiovascular risk in the aging cardiovascular system. L-arginine, the NO synthase substrate, improves endothelial dependent vasodilatation by unknown mechanism(s), since intracellular concentrations of L-arginine far exceed the Kd for nitric oxide synthase (NOS). The observation that L-arginine administration increases NO synthesis and enhances endothelial function even in the setting of apparently adequate L-arginine levels in the cell has come to be called the "L-arginine paradox". Arginase, an enzyme of the urea cycle also uses L-arginine as a substrate and is present in cardiovascular tissue. Our preliminary data demonstrate that the L-arginine metabolizing enzyme, arginase, reciprocally regulates vascular endothelial NOS activity, and directly influences vascular relaxation in rats. Furthermore, arginase activity and expression are increased in agingrat vessels, and arginase inhibition attenuates the increased reactive oxygen species (ROS) produced in old rat vascular tissue. We hypothesize that: 1) endothelial arginase limits endothelial NO production and thus, endothelial-dependent vasodilatation, by competing for intracellular L-arginine; 2) vascular endothelial dysfunction of aging is associated with increased expression of endothelial arginase, and inhibition of arginase restores NO-dependent signaling and endothelial function to that of the young phenotype; 3) relative substrate (L-arginine) deficiency enhances ROS production further compromising endothelial function by altering the balance between NO and 02-; and 4) chronic arginase inhibition will restore Larginine reponsiveness, enhance NO signaling, and decrease ROS production thereby restoring altered integrated cardiovascular parameters (increased vascular and ventricular stiffness and altered ventriculararterial coupling) to that of the young phenotype. We will study the regulatory role of arginase in normal endothelial function and NO signaling, as well as its role in the pathophysiology of endothelial dysfunction associated with aging. These experiments will offer novel insights into regulation of the NO signaling pathway, and the balance between NO and 02- in endothelial function, with important therapeutic implications for a wide variety of disorders characterized by endothelial dysfunction.